The orphan G protein–coupled receptor, GPRC5D, has been identified in bone marrow cells in patients with multiple myeloma (MM). Talquetamab, a first-in-class bispecific antibody, binds to both GPRC5D on MM cells and CD3 on T-lymphocytes, to induce immunologically mediated killing of MM cells. Initial results from an ongoing phase 1 dose-escalation study are presented.
Patients were required to have measurable MM that either progressed, or for which other established therapies were not viable. The primary objectives were to assess the safety of talquetamab and to identify a dose for phase 2 investigation. Secondary objectives were to assess the pharmacokinetics, pharmacodynamics, and preliminary efficacy. Escalating doses of talquetamab (both intravenous [IV] and subcutaneous [SC]) ± step-up doses were assessed.
Patients received IV talquetamab (0.5-180 μg/kg; n = 102) or SC talquetamab (5-800 μg/kg; n = 55). The median age was 64 years, and 30% of patients were aged ≥70 years. Patients had received a median of 6 prior therapies over a median of 6.5 years since diagnosis; 87% were refractory to the last line of therapy received, 82% were triple-class refractory, 76% were penta-drug exposed, and 33% were penta-drug refractory. Seventeen percent (n = 27) had received B-cell maturation antigen–directed therapy.
The most frequent all-grade adverse events (AEs) were anemia, cytokine-release syndrome (CRS), neutropenia, and lymphopenia, occurring in 48%, 54%, 47%, and 40% of patients, respectively. The most common grade 3/4 AEs were lymphopenia, anemia, and neutropenia, occurring in 36%, 27%, and 31% of patients, respectively. All CRS AEs with SC dosing were grade 1/2; CRS events with IV dosing were mostly grade 1/2, except for in 5 patients (grade 3). CRS generally occurred in Cycle 1 and had a median time to onset of 1 day for IV and 2 days for SC dosing. Six percent of patients (n = 9) experienced treatment-related neurotoxicity. Thirty-eight percent of patients experienced infections (8% grade 3/4). Infusion-related reactions and injection-site reactions were experienced by 18% of patients, and were grade 1/2. Three dose-limiting toxicities occurred: clinically asymptomatic grade 4 increased lipase in the setting of a pancreatic plasmacytoma with 7.5 μg/kg IV talquetamab, and grade 3 maculopapular rash with 135 μg/kg SC talquetamab (n = 2). The maximum tolerated dose has not been identified.
Weekly IV dosing is supported by the half-life of talquetamab. A linear dose-response curve was observed following the first IV dose (1.5-60 μg/kg). A lower maximum serum concentration was observed with SC versus IV dosing, but trough levels were comparable at similar doses. Comparable increases in T-cell activation and plasma cytokine levels were observed with IV and SC dosing. Step-up dosing was effective at modulating cytokine production while maintaining T-cell activation.
The overall response rate (ORR) was 67% (12/18) for talquetamab IV 20 μg/kg to 180 μg/kg. The ORR was 66% (21/32) for talquetamab SC 135 μg/kg to 405 μg/kg. Responses began at doses as low as 1.0 μg/kg and were rapid (median, 1 month) and durable.
Results from this phase 1 first-in-human study of talquetamab showed encouraging clinical activity with manageable toxicity in heavily pretreated patients with relapsed/refractory MM. The study is ongoing to identify a dose for phase 2 investigation.
Reference
Abstract 290. ASH 2020. December 5, 2020. A Phase 1, First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) x CD3 Bispecific Antibody, in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM).